Despite improvements in early post-transplant survival rates over the last two decades, a relentless annualattrition of 3-5% in recipients of previously functioning organ allografts continues to limit longer term outcomes. Success rates following pancreatic islet transplantation are even less acceptable. The major objectives of this multi-project research Program are to improve the long-term outcome following kidney and kidney/islet transplantation for both living and deceased donor transplants. We intend to investigate, in clinically relevant NHP models 1) the conditions necessary for consistent induction of durable allograft tolerance for both living and deceased donor transplants; 2) the genetic and technical parameters required for successful composite IK transplants from living donors; and 3) the immunological mechanisms involved in tolerance of kidney, islet, and islet-kidney (IK) allografts. Clinical translation of therapeutic protocols for reliably achieving donor-specific immunologic non-responsiveness would eliminate much of the currently observed annual attrition of transplanted organs and tissues as well as the morbidities associated with the administration of lifelong immunosuppressive agents. We have previously shown that allograft tolerance can be induced in NHP via several approaches, one of which (mixed chimerism) we have extended to humans. In those seminal trials, long-term (2-8yrs) immunosuppression-free, stable renal function has been achieved in 7/10 initial recipients of HLA mismatched live-donor renal allografts selected for study. Although this achievement is dramatic, it is currently reliant upon conditioning, the application of which is limited to living donor recipients (beginning 6 days pre-transplant) and to a tolerogenic organ (kidney). The main hypotheses to be pursued in this Program are: 1) that reproducible induction of more robust and durable chimerism or cotransplantation of the kidney with islets will extend the application of this means of tolerance induction to a much wider population of allograft recipients, including those of deceased-donor kidneys and of islets, and, 2) that the current protocol can be effectively extended to islets from a living donor if the islet are included as part of a composite IK allograft. The studies planned will clarify the mechanisms involved with tolerance induction via the mixed chimerism approach and define the parameters that will allow rapid translation of these clinically relevant observations to treatment of diabeti patients who are candidates for kidney/pancreas transplantation.